Internalization and Processing of Human Angiogenin by Cultured Aortic Smooth Muscle Cells

Hatzi, Elissavet; Bassaglia, Yann; Badet, Josette

doi:10.1006/bbrc.1999.2015

Cited by 9 publications

(7 citation statements)

References 32 publications

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“…The majority of the circulating ANG is produced by the liver (29). Moreover, with a seeming fast turnover rate and a half-life of 2 h (30), a large quantity of ANG inhibitors would be needed to neutralize the circulating ANG.…”

Section: Discussionmentioning

confidence: 99%

Neamine Inhibits Prostate Cancer Growth by Suppressing Angiogenin-Mediated rRNA Transcription

Ibaragi

Yoshioka

et al. 2009

Clinical Cancer Research

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Purpose: Angiogenin (ANG) undergoes nuclear translocation and stimulates rRNA transcription in both prostate cancer cells and endothelial cells. The purpose of this study is to assess the antitumor activity of neamine, a nontoxic degradation product of neomycin that blocks nuclear translocation of ANG. Experimental Design: The anti-prostate cancer activity of neamine was first evaluated in a xenograft animal model. It was then examined in the murine prostate-restricted AKT transgenic mice that develop prostate intraepithelial neoplasia (PIN) owing to AKT transgene overexpression. Results: Neamine inhibits xenograft growth of PC-3 human prostate cancer cells in athymic mice. It blocks nuclear translocation of ANG and inhibits rRNA transcription, cell proliferation, and angiogenesis. Neamine also prevents AKT-induced PIN formation as well as reverses fully developed PIN in murine prostate-restricted AKT mice, accompanied by a decrease in rRNA synthesis, cell proliferation, and angiogenesis and an increase in prostate epithelial cell apoptosis. Conclusion: We confirmed that ANG is a molecular target for cancer drug development and that blocking nuclear translocation of ANG is an effective means to inhibit its activity. Our results also suggested that neamine is a lead compound for further preclinical evaluation.

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Section: Discussionmentioning

confidence: 99%

Neamine Inhibits Prostate Cancer Growth by Suppressing Angiogenin-Mediated rRNA Transcription

Ibaragi

Yoshioka

et al. 2009

Clinical Cancer Research

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“…The majority of the circulating ANG is produced by the liver [23]. Moreover, with a seemingly fast turnover rate and a half-life of 2 h [34], a large quantity of ANG inhibitors would be needed to neutralize the circulating ANG.…”

Section: Ang As a Molecular Target For Prostate Cancer Drug Developmentmentioning

confidence: 99%

Angiogenin as a Molecular Target for the Treatment of Prostate Cancer

Li¹,

Ibaragi²,

Hu³

2011

CCTR

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Angiogenin (ANG), a 14 kDa angiogenic ribonuclease, is upregulated in human prostate cancers, especially in hormone refractory diseases, and is the highest upregulated gene in Akt-driven prostate intraepithelial neoplasia (PIN) in mice. ANG has been shown to undergo nuclear translocation in both prostate cancer cells and cancer-associated endothelial cells where it binds to the promoter region of ribosomal DNA (rDNA) and stimulates ribosomal RNA (rRNA) transcription. ANG thus plays an essential role in prostate cancer progression by stimulating both cancer cell proliferation and tumor angiogenesis. A variety of ANG antagonists, including its antisense oligonucleotide, siRNA, soluble binding proteins, monoclonal antibody, enzymatic inhibitors, and nuclear translocation blockers, have all been shown to inhibit prostate cancer in various animal models. Accumulating evidence indicates that ANG is a molecular target for prostate cancer drug development.

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“…In order to reach the nucleus, a secreted protein has to be internalized back to the cytoplasm or, in the case of IPSE/alpha-1, into the cytoplasm of host cells. This may involve endocytosis-dependent processes, as reported for angiogenin (23) and parathyroid hormone-related protein (PtHrP) (3). Using standard approaches, we have demonstrated that IPSE/alpha-1 contains a monopartite functional NLS motif (PKRRRTY) that is necessary and sufficient for its translocation to the nucleus.…”

mentioning

confidence: 99%

Interleukin-4-Inducing Principle from Schistosoma mansoni Eggs Contains a Functional C-Terminal Nuclear Localization Signal Necessary for Nuclear Translocation in Mammalian Cells but Not for Its Uptake

et al. 2011

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Interleukin-4-inducing principle from schistosome eggs (IPSE/alpha-1) is a protein produced exclusively by the eggs of the trematode Schistosoma mansoni. IPSE/alpha-1 is a secretory glycoprotein which activates human basophils via an IgE-dependent but non-antigen-specific mechanism. Sequence analyses revealed a potential nuclear localization signal (NLS) at the C terminus of IPSE/alpha-1. Here we show that this sequence (125-PKRRRTY-131) is both necessary and sufficient for nuclear localization of IPSE or IPSE-enhanced green fluorescent protein (EGFP) fusions. While transiently expressed EGFP-IPSE/alpha-1 was exclusively nuclear in the Huh7 and U-2 OS cell lines, a mutant lacking amino acids 125 to 134 showed both nuclear and cytoplasmic staining. Moreover, insertion of the IPSE/alpha-1 NLS into a tetra-EGFP construct rendered the protein nuclear. Alanine scanning mutagenesis revealed a requirement for the KRRR residues. Fluorescence microscopy depicted, and Western blotting further confirmed, that recombinant IPSE/alpha-1 protein added exogenously is rapidly internalized by CHO cells and accumulates in nuclei in an NLS-dependent manner. A mutant protein in which the NLS motif was disrupted by triple mutation (RRR to AAA) was able to penetrate CHO cells but did not translocate to the nucleus. Furthermore, the uptake of native glycosylated IPSE/alpha-1 was confirmed in human primary monocyte-derived dendritic cells and was found to be a calcium-and temperature-dependent process. Live-cell imaging showed that IPSE/alpha-1 is not targeted to lysosomes. In contrast, peripheral blood basophils do not take up IPSE/alpha-1 and do not require the presence of an intact NLS for activation. Taken together, our results suggest that IPSE/alpha-1 may have additional nuclear functions in host cells.

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Internalization and Processing of Human Angiogenin by Cultured Aortic Smooth Muscle Cells

Cited by 9 publications

References 32 publications

Neamine Inhibits Prostate Cancer Growth by Suppressing Angiogenin-Mediated rRNA Transcription

Neamine Inhibits Prostate Cancer Growth by Suppressing Angiogenin-Mediated rRNA Transcription

Angiogenin as a Molecular Target for the Treatment of Prostate Cancer

Interleukin-4-Inducing Principle from Schistosoma mansoni Eggs Contains a Functional C-Terminal Nuclear Localization Signal Necessary for Nuclear Translocation in Mammalian Cells but Not for Its Uptake

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